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Central role of mTORC1 downstream of YAP/TAZ in hepatoblastoma development
Hepatoblastoma (HB) is the most common type of liver malignancy in children. Recent studies suggest that activation of Yes-associated protein (YAP) is a major molecular event in HB development, as activated YAP synergizes with mutant β-catenin to promote HB formation in mice (YAP/β-catenin). However...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5650273/ https://www.ncbi.nlm.nih.gov/pubmed/29088718 http://dx.doi.org/10.18632/oncotarget.20622 |
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author | Liu, Pin Calvisi, Diego F. Kiss, Andras Cigliano, Antonio Schaff, Zsuzsa Che, Li Ribback, Silvia Dombrowski, Frank Zhao, Dongchi Chen, Xin |
author_facet | Liu, Pin Calvisi, Diego F. Kiss, Andras Cigliano, Antonio Schaff, Zsuzsa Che, Li Ribback, Silvia Dombrowski, Frank Zhao, Dongchi Chen, Xin |
author_sort | Liu, Pin |
collection | PubMed |
description | Hepatoblastoma (HB) is the most common type of liver malignancy in children. Recent studies suggest that activation of Yes-associated protein (YAP) is a major molecular event in HB development, as activated YAP synergizes with mutant β-catenin to promote HB formation in mice (YAP/β-catenin). However, how YAP regulates HB development remains poorly defined. Similarly, de-regulation of mammalian target of rapamycin complex 1 (mTORC1) signaling has been implicated in multiple tumor types, but its functional role in HB development is scarcely understood. In the present study, we found that mTORC1 is activated in human HB cells and YAP/β-catenin-induced mouse HB tumor tissues. mTOR inhibitor MLN0128 significantly inhibits human HB cell growth in vitro. Furthermore, ablation of Raptor, the unique subunit of mTORC1, strongly delayed YAP/β-catenin-induced HB development in mice. At the molecular level, we found that expression of the amino acid transporter SLC38A1 is induced in mouse HB tissues, and amino acid deprivation leads to mTORC1 suppression in HB cell lines. Silencing of YAP and/or its paralog, transcriptional co-activator with PDZ binding motif (TAZ), decreased SLC38A1 expression as well as mTORC1 activation in HB cells. Furthermore, a frequent and concomitant upregulation of mTORC1 and SLC38A1 was detected in a collection of human HB specimens. Altogether, our study demonstrates the key role of mTORC1 in HB development. YAP and TAZ promote HB development via inducing SLC38A1 expression, whose upregulation leads to mTORC1 activation. Targeting mTOR pathway or amino acid transporters may represent novel therapeutic strategies for the treatment of human HB. |
format | Online Article Text |
id | pubmed-5650273 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-56502732017-10-30 Central role of mTORC1 downstream of YAP/TAZ in hepatoblastoma development Liu, Pin Calvisi, Diego F. Kiss, Andras Cigliano, Antonio Schaff, Zsuzsa Che, Li Ribback, Silvia Dombrowski, Frank Zhao, Dongchi Chen, Xin Oncotarget Priority Research Paper Hepatoblastoma (HB) is the most common type of liver malignancy in children. Recent studies suggest that activation of Yes-associated protein (YAP) is a major molecular event in HB development, as activated YAP synergizes with mutant β-catenin to promote HB formation in mice (YAP/β-catenin). However, how YAP regulates HB development remains poorly defined. Similarly, de-regulation of mammalian target of rapamycin complex 1 (mTORC1) signaling has been implicated in multiple tumor types, but its functional role in HB development is scarcely understood. In the present study, we found that mTORC1 is activated in human HB cells and YAP/β-catenin-induced mouse HB tumor tissues. mTOR inhibitor MLN0128 significantly inhibits human HB cell growth in vitro. Furthermore, ablation of Raptor, the unique subunit of mTORC1, strongly delayed YAP/β-catenin-induced HB development in mice. At the molecular level, we found that expression of the amino acid transporter SLC38A1 is induced in mouse HB tissues, and amino acid deprivation leads to mTORC1 suppression in HB cell lines. Silencing of YAP and/or its paralog, transcriptional co-activator with PDZ binding motif (TAZ), decreased SLC38A1 expression as well as mTORC1 activation in HB cells. Furthermore, a frequent and concomitant upregulation of mTORC1 and SLC38A1 was detected in a collection of human HB specimens. Altogether, our study demonstrates the key role of mTORC1 in HB development. YAP and TAZ promote HB development via inducing SLC38A1 expression, whose upregulation leads to mTORC1 activation. Targeting mTOR pathway or amino acid transporters may represent novel therapeutic strategies for the treatment of human HB. Impact Journals LLC 2017-09-01 /pmc/articles/PMC5650273/ /pubmed/29088718 http://dx.doi.org/10.18632/oncotarget.20622 Text en Copyright: © 2017 Liu et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Priority Research Paper Liu, Pin Calvisi, Diego F. Kiss, Andras Cigliano, Antonio Schaff, Zsuzsa Che, Li Ribback, Silvia Dombrowski, Frank Zhao, Dongchi Chen, Xin Central role of mTORC1 downstream of YAP/TAZ in hepatoblastoma development |
title | Central role of mTORC1 downstream of YAP/TAZ in hepatoblastoma development |
title_full | Central role of mTORC1 downstream of YAP/TAZ in hepatoblastoma development |
title_fullStr | Central role of mTORC1 downstream of YAP/TAZ in hepatoblastoma development |
title_full_unstemmed | Central role of mTORC1 downstream of YAP/TAZ in hepatoblastoma development |
title_short | Central role of mTORC1 downstream of YAP/TAZ in hepatoblastoma development |
title_sort | central role of mtorc1 downstream of yap/taz in hepatoblastoma development |
topic | Priority Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5650273/ https://www.ncbi.nlm.nih.gov/pubmed/29088718 http://dx.doi.org/10.18632/oncotarget.20622 |
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